The preocular tear film plays an essential role in the maintenance of corneal integrity, the protection against microbial challenge and the preservation of visual acuity (1). These functions, in turn, are critically dependent upon the stability, tonicity and/or composition of the tear film structure, which includes an underlying mucin foundation, a substantial, middle aqueous component and an overlying lipid layer (1,2). Alteration, deficiency or absence of the tear film may lead to intractable desiccation of the corneal epithelium, ulceration and perforation of the cornea, an increased incidence of infectious disease, and ultimately, severe visual impairment and blindness (2,3).
Throughout the world, countless individuals suffer from tear film dysfunctions, which are collectively diagnosed as keratoconjunctivitis sicca (KCS) or, simply, dry eye (1,2). These lacrimal abnormalities may be subdivided into four general categories: (a) aqueous tear deficiencies, which are most frequently responsible for dry eye states, originate from lacrimal gland disorders and include autoimmune disease, congenital alacrima, paralytic hyposecretion or excretory duct obstruction; (b) mucin deficiency, which is observed in various conjunctival cicatrization conditions, such as Stevens-Johnson syndrome, trachoma, pemphigoid, thermal and chemical burns, as well as hypovitaminosis A; (c) lipid abnormalities, which may occur during eyelid inflammation (e.g. chronic blepharitis); and (d) diminished eyelid function (1).
By far, the greatest single cause of KCS worldwide, excluding those countries wherein trachoma remains epidemic, is Sj ogren's syndrome (2). This syndrome, which is the second most common autoimmune disease (7,14), occurs almost exclusively in females and is characterized by an insidious and progressive lymphocytic infiltration into the main and accessory lacrimal glands, an immune-mediated, extensive destruction of lacrimal acinar and ductal tissues and the consequent development of persistent KCS (7-10). In primary Sj ogren's syndrome, which afflicts about 50% of the patient population, the disease is also associated with an immunological disruption of the salivary gland and pronounced xerostomia. In secondary Sj ogren's, the disorder is accompanied by another disease, which is most often rheumatoid arthritis and less frequently systemic lupus erythematosus (SLE), scleroderma, polymyositis, polyarteritis nodosa, Hashimoto's thyroiditis, chronic hepatobiliary disease, chronic pulmonary fibrosis, purpura hyperglobulinemia or Raynaud's phenomenon (2,11). During the course of Sj ogren's syndrome, autoimmune sequelae may also encompass focal lymphocytic adenitis of eccrine and mucosal glands, biliary cirrhosis, sclerosing cholangitis, pancreatitis, atrophic gastritis, interstitial nephritis and pneumonitis, peripheral vasculitis, B cell lymphoma and a diverse array of central and peripheral nervous system and skeletal muscle complications (12,13).
The etiology of Sj ogren's syndrome may be due to the interaction of numerous factors, including those of genetic, endocrine, neural, viral and environmental origin (15,16). However, a potential cause may relate to primary infection by, and reactivation of, Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV) (17-20). These herpes viruses are present in lacrimal and salivary glands of Sj ogren's patients (17-20) and may induce the inappropriate HLA-DR expression, T helper/inducer cell activation, B cell hyperactivity and autoantibody production evident in these affected tissues (8). However, whether herpes, or even retroviral (21,22), action represents a cause of, or merely an epiphenomenon in, Sj ogren's syndrome remains to be determined (23-25).
At present, a perception is that Sj ogren's syndrome may be clinically irreversible (7), an autoimmune disease to be controlled, yet not cured (10). In the scientific literature, reports have suggested that systemic or topical administration of estrogens (4), cyclosporine A (6) or glucocorticoids (26) might alleviate the ocular manifestations of this disorder. However, other studies indicate that such pharmaceutical exposures are ineffective (27-29) and, in fact, may accelerate and/or amplify the disease (28,30). Indeed, estrogen action may be involved in the etiology of Sj ogren's syndrome (30,31).
Others have suggested that tear stimulants, such as bromhexine (32) or isobutylmethylxanthine (33), might improve ocular symptoms. These drug effects, though, may be subjective (34), susceptible to tachyphylaxis (4) and/or limited by the requirement for functional and responsive lacrimal tissue (4,35).
It has also been proposed that systemic androgen treatment might provide a potential therapy for Sj ogren's syndrome and its associated defects. This proposal is based upon the finding that autoimmune disorders commonly display a sexual dichotomy, with estrogens increasing disease severity in females and androgens suppressing autoimmune sequelae in males (15,16,36-38). In fact, systemic androgen therapy has been utilized to effectively diminish autoimmune expression in animals models of SLE, thyroiditis, polyarthritis and myasthenia gravis (15,38-43), as well as the human condition of idiopathic thrombocytopenic purpura (44). However, research has also demonstrated that the systemic administration of androgens to patients with primary or secondary Sj ogren's syndrome or SLE is apparently unable to correct various peripheral manifestations of these disorders (49,54,55,62). In addition, systemic androgen treatment of female patients with Sj ogren's syndrome exposes these individuals to possible undesirable side effects, including virilization, menstrual irregularities (e.g., amenorrhea), hepatic dysfunction, edema, hematologic abnormalities, behavioral changes and metabolic alterations. Similarly, chronic treatment of males with systemic androgens has been characterized as dangerous (63), because of the numerous potential side effects. For these reasons, a recent report has indicated that systemic androgen therapy is inappropriate for the treatment of the multiple immune dysfunctions in Sj ogren's syndrome (63).
Others have suggested that anti-viral compounds may represent a new therapeutic approach for ocular disease in Sj ogren's syndrome. Researchers have speculated that such compounds may be effective in counteracting the viral (e.g., EBV- and/or CMV)-induced infection in lacrimal tissue, that may possibly precipitate the gland's immune-associated dysfunction (17,19,20). The potential efficacy of this strategy, though, is highly speculative: current scientific information does not show definitively that these viruses are directly involved in the pathogenesis or progression of Sj ogren's syndrome (23-25).
Therefore, the currently prescribed, therapeutic approach for the management of KCS in Sj ogren's syndrome is the frequent application of artificial tear substitutes, which permit lubrication of the eye's anterior surface (3,4,5,9,10). Unfortunately, this therapy does not represent a cure and does not ameliorate the inherent, ocular immunopathology and resulting KCS associated with this chronic, extremely uncomfortable and vision-threatening disease (3).